4,7-benzofurandione derivatives

ABSTRACT

4,7-Benzofurandione derivatives of Formula I, pharmaceutical compositions, and methods of treatment are disclosed. These compounds are useful as inhibitors of mammalian leukotriene biosynthesis. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders, inflammation, psoriasis and allergic conjunctivitis. The compounds are also useful as analgesics and as cytoprotective agents. Also disclosed are novel intermediates useful for the preparation of the 4,7-benzofurandiones of this invention. ##STR1##

BACKGROUND OF THE INVENTION

This is a division of Ser. No. 64,152, Jun. 18, 1987, now U.S. Pat. No. 4,778,805.

U.S. Pat. No. 4,778,805, Adams et al., is incorporated herein in its entirety.

SUMMARY OF THE INVENTION

It has now been discovered that certain tetrasubstituted benzofurandiones of Formula I are effective inhibitors of leukotriene biosynthesis. Thus, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders such as angina, inflammation, for amelioration of skin diseases like psoriasis and atopic eczema, for treatment of allergic conjunctivitis, as analgesics, and as cytroprotective agents.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are compounds of the formula: ##STR2## --(CR⁵ R⁵)_(s) --(X¹)_(t) --(CR⁵ R⁵)_(u) --CO₂ R⁶ ; or lower alkyl;

R² is lower alkyl;

R³ and R⁴ are each independently R², Cl, X² R², or X³ R⁵ ;

R⁵ is H or lower alkyl, or two R⁵ 's when attached to N may be joined to form a 5- or 6-membered ring;

R⁶ is H or lower alkyl;

R⁷ is H or lower alkyl;

R⁸ is H or lower alkyl;

X¹ is X² or X³ ;

X² is S, S(O), S(O)₂ ;

X³ is O or NR⁵ ;

X⁴ is X² or X³

Y¹ and Y² are each independently: H, R², X² R², X³ R⁵, halogen, (X⁴)_(w) --(CR⁵ R⁵)_(z) --CO₂ R⁷, CF₃, COR⁸, CONR⁵ R⁵, or S(O₂)NR⁵ R⁵ ; or Y¹ and Y² may be joined to form a 5- or 6-membered ring, containing one or two O atoms, such as --OCH₂ O, --OCH₂ CH₂ O--, --OCH₂ CH₂ -- or --OCH₂ CH₂ CH₂ --;

1 and n are each independently 0 to 5;

m is 0 to 1;

s is 0 to 3;

u is 0 to 3 provided that when t is 1 and R⁶ is H, then u is 1 to 3;

t is 0 or 1;

w is 0 or 1; and

z is 0 to 3, provided that when w is 1 and R⁷ is H, then z is 1 to 3;

and the pharmaceutically acceptable salts thereof.

A preferred embodiment of the present invention is represented by Formula Ia: ##STR3## wherein:

R³ is R²

R⁴ is R² or X³ R⁵

n is 0 or 1 and the remaining substuents are as defined for Formula I.

Another preferred embodiment of the present information is that wherein:

R¹ is lower alkyl;

R³ and R⁴ are each independently R², X² R², or X³ R⁵ ;

and the remaining substituents are as defined for Formula I.

A further embodiment of this invention are novel di- and tri-substituted compounds of Formula Ib useful as intermediate for the preparation of Formula I compounds. These compounds are represented in Table 2.

                  TABLE 2                                                          ______________________________________                                          ##STR4##                      Ib                                              Ex. No.   R.sup.1     Y.sup.1     Y.sup.2                                                                            R.sup.3                                  ______________________________________                                         25        CO.sub.2 Et --          --  H                                        26        CO.sub.2 Et --          --  n-Pr                                     27        H           --          --  n-Pr                                     28        CH.sub.2 C.sub.6 H.sub.3 Y.sup.1 Y.sup.2                                                   4-OMe       H   n-Pr                                     29        CH.sub.2 C.sub.6 H.sub.3 Y.sup.1 Y.sup.2                                                   4-OH        H   n-Pr                                     30        CH.sub.2 C.sub.6 H.sub.3 Y.sup.1 Y.sup.2                                                   4-OMe       H   H                                        31        CH.sub.2 CO.sub.2 Et                                                                       --          --  n-Pr                                     ______________________________________                                     

What is claimed is:
 1. A compound of the Formula Ib:

    ______________________________________                                          ##STR5##                      Ib                                              R.sup.1        Y.sup.1    Y.sup.2  R.sup.3                                     ______________________________________                                         CO.sub.2 Et    --         --       H                                           CO.sub.2 Et    --         --       n-Pr                                        H              --         --       n-Pr                                        CH.sub.2 C.sub.6 H.sub.3 Y.sup.1 Y.sup.2                                                      4-OMe      H        n-Pr                                        CH.sub.2 C.sub.6 H.sub.3 Y.sup.1 Y.sup.2                                                      4-OH       H        n-Pr                                        CH.sub.2 C.sub.6 H.sub.3 Y.sup.1 Y.sup.2                                                      4-OMe      H        H                                           CH.sub.2 CO.sub.2 Et                                                                          --         --       n-Pr                                        ______________________________________                                     